# Regulatory mechanisms of deer antler extracellular vesicles in multilevel tissue repair: a state-of-the-art review

**Authors:** Lei Yuan, Bowen Deng, Fengrui Zhang, Deyou Wang, Haiyan Chen

PMC · DOI: 10.3389/fphar.2026.1758263 · Frontiers in Pharmacology · 2026-02-19

## TL;DR

This review explores how deer antler extracellular vesicles can promote tissue repair through multiple mechanisms, offering potential for regenerative medicine.

## Contribution

The paper provides a comprehensive review of the regenerative mechanisms and future engineering strategies of deer antler-derived extracellular vesicles.

## Key findings

- Deer antler EVs regulate stem cell proliferation and differentiation at the cellular level.
- They modulate immune cell activity and cytokine networks in the tissue microenvironment.
- EVs influence key signaling pathways like Wnt/β-catenin and TGF-β for tissue regeneration.

## Abstract

Extracellular vesicles (EVs) are defined as key nanoscale messengers that mediate intercellular communication, demonstrating immense potential in tissue repair and regenerative medicine. As the only organ in mammals capable of complete, cyclical regeneration, deer antlers provide EVs with exceptional regenerative bioactivity. This paper systematically reviews and prospectively discusses the research field of deer antler-derived EVs. We first outline their isolation strategies and characteristic functional subtypes, then focus on elucidating their multi-level molecular mechanisms driving tissue repair: at the cellular level, they directly regulate stem cell proliferation and lineage differentiation; at the microenvironmental level, they effectively remodel the immune ecology of injured areas by reprogramming immune cells and coordinating cytokine networks, thereby creating favorable conditions for regeneration. At the molecular level, they precisely regulate core signaling pathways, including the Wnt/β-catenin, NF-κB, miR-21-5p/STAT3, and TGF-β pathways. Finally, this paper prospectively explores cutting-edge developments in the field, including enhancing vesicle targeting and drug-loading capacity through engineering strategies, constructing controlled-release delivery systems based on smart materials, and developing precision therapies tailored to specific pathological microenvironments. This review aims to elucidate the biomedical potential of deer antler extracellular vesicles as regenerative nanomedicines for promoting tissue repair.

## Full-text entities

- **Genes:** Runx2 (RUNX family transcription factor 2) [NCBI Gene 367218] {aka CBF-alpha-1, Cbfa1, OSF-2}, IL4 (interleukin 4) [NCBI Gene 3565] {aka BCGF-1, BCGF1, BSF-1, BSF1, IL-4}, DNMT3A (DNA methyltransferase 3 alpha) [NCBI Gene 1788] {aka DNMT3A2, HESJAS, M.HsaIIIA, TBRS}, Ctnnb1 (catenin beta 1) [NCBI Gene 84353] {aka Catnb}, Wnt2 (Wnt family member 2) [NCBI Gene 114487] {aka Wnt}, TGFBR1 (transforming growth factor beta receptor 1) [NCBI Gene 7046] {aka AAT5, ACVRLK4, ALK-5, ALK5, ESS1, LDS1}, MAPK14 (mitogen-activated protein kinase 14) [NCBI Gene 1432] {aka CSBP, CSBP1, CSBP2, CSPB1, EXIP, Mxi2}, ANGPT1 (angiopoietin 1) [NCBI Gene 284] {aka AGP1, AGPT, AGPT-1, ANG1, HAE5}, IKBKB (inhibitor of nuclear factor kappa B kinase subunit beta) [NCBI Gene 3551] {aka IKK-2, IKK-beta, IKK2, IKKB, IMD15, IMD15A}, NFKBIA (NFKB inhibitor alpha) [NCBI Gene 4792] {aka EDAID2, IKBA, MAD-3, NFKBI}, SMAD3 (SMAD family member 3) [NCBI Gene 4088] {aka HSPC193, HsT17436, JV15-2, LDS1C, LDS3, MADH3}, MIR18A (microRNA 18a) [NCBI Gene 406953] {aka C13orf25, MIR18, MIRH1, MIRHG1, MIRN18, MIRN18A}, Bcl2 (BCL2, apoptosis regulator) [NCBI Gene 24224] {aka Bcl-2}, PRG4 (proteoglycan 4) [NCBI Gene 10216] {aka CACP, HAPO, JCAP, MSF, SZP}, THY1 (Thy-1 cell surface antigen) [NCBI Gene 7070] {aka CD90, CDw90}, HNF4A (hepatocyte nuclear factor 4 alpha) [NCBI Gene 3172] {aka FRTS4, HNF4, HNF4a7, HNF4a8, HNF4a9, HNF4alpha}, PTEN (phosphatase and tensin homolog) [NCBI Gene 5728] {aka 10q23del, BZS, CWS1, DEC, GLM2, MHAM}, CCND1 (cyclin D1) [NCBI Gene 595] {aka BCL1, D11S287E, PRAD1, U21B31}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, MIR140 (microRNA 140) [NCBI Gene 406932] {aka MIRN140, SEDN, miRNA140, mir-140}, SMAD4 (SMAD family member 4) [NCBI Gene 4089] {aka DPC4, JIP, MADH4, MYHRS}, RUNX2 (RUNX family transcription factor 2) [NCBI Gene 860] {aka AML3, CBF-alpha-1, CBFA1, CCD, CCD1, CLCD}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, Il6 (interleukin 6) [NCBI Gene 24498] {aka ILg6, Ifnb2}, Bax (BCL2 associated X, apoptosis regulator) [NCBI Gene 24887], RELB (RELB proto-oncogene, NF-kB subunit) [NCBI Gene 5971] {aka I-REL, IMD53, IREL, REL-B}, Gap43 (growth associated protein 43) [NCBI Gene 29423] {aka Basp2}, FSD1 (fibronectin type III and SPRY domain containing 1) [NCBI Gene 79187] {aka GLFND, MIR1}, MMP2 (matrix metallopeptidase 2) [NCBI Gene 4313] {aka CLG4, CLG4A, MMP-2, MMP-II, MONA, TBE-1}, IKBKG (inhibitor of nuclear factor kappa B kinase regulatory subunit gamma) [NCBI Gene 8517] {aka AMCBX1, EDAID1, FIP-3, FIP3, Fip3p, IKK-gamma}, PRKAR2A (protein kinase cAMP-dependent type II regulatory subunit alpha) [NCBI Gene 5576] {aka PKR2, PRKAR2}, MIR210 (microRNA 210) [NCBI Gene 406992] {aka MIRN210, mir-210}, MAP2K7 (mitogen-activated protein kinase kinase 7) [NCBI Gene 5609] {aka JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7}, Smad7 (SMAD family member 7) [NCBI Gene 81516] {aka Madh7}, BMP2 (bone morphogenetic protein 2) [NCBI Gene 650] {aka BDA2, BMP2A, SSFSC, SSFSC1}, MIR215 (microRNA 215) [NCBI Gene 406997] {aka MIRN215, miRNA215, mir-215}, Mir215 (microRNA 215) [NCBI Gene 100314074] {aka rno-mir-215}, ARG1 (arginase 1) [NCBI Gene 383], TIMP3 (TIMP metallopeptidase inhibitor 3) [NCBI Gene 7078] {aka HSMRK222, K222, K222TA2, SFD}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, GSK3B (glycogen synthase kinase 3 beta) [NCBI Gene 2932], VWF (von Willebrand factor) [NCBI Gene 7450] {aka F8VWF, VWD}, MMP1 (matrix metallopeptidase 1) [NCBI Gene 4312] {aka CLG}, ZHX2 (zinc fingers and homeoboxes 2) [NCBI Gene 22882] {aka AFR1, RAF}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, IL13 (interleukin 13) [NCBI Gene 3596] {aka IL-13, P600}, PPARG (peroxisome proliferator activated receptor gamma) [NCBI Gene 5468] {aka CIMT1, FPLD3, GLM1, NR1C3, PPARG1, PPARG2}, MIR18B (microRNA 18b) [NCBI Gene 574033] {aka MIRN18B, hsa-mir-18b, mir-18b}, Il10 (interleukin 10) [NCBI Gene 25325] {aka IL10X, If2a}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 59086] {aka Tgfb}, PDCD4 (programmed cell death 4) [NCBI Gene 27250] {aka H731}, Syt1 (synaptotagmin 1) [NCBI Gene 25716] {aka P65}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, LGALS1 (galectin 1) [NCBI Gene 3956] {aka GAL1, GBP}, CXCL8 (C-X-C motif chemokine ligand 8) [NCBI Gene 3576] {aka GCP-1, GCP1, IL8, LECT, LUCT, LYNAP}, PYCARD (PYD and CARD domain containing) [NCBI Gene 29108] {aka ASC, CARD5, TMS, TMS-1, TMS1}, WNT3A (Wnt family member 3A) [NCBI Gene 89780], INHBE (inhibin subunit beta E) [NCBI Gene 83729], COL1A1 (collagen type I alpha 1 chain) [NCBI Gene 1277] {aka CAFYD, EDSARTH1, EDSC, OI1, OI2, OI3}, CD81 (CD81 molecule) [NCBI Gene 975] {aka CVID6, S5.7, TAPA1, TSPAN28}
- **Diseases:** femoral defect (MESH:D005266), hypoxia (MESH:D000860), burn (MESH:D002056), cartilage defect (MESH:D002357), necrotic tissue (MESH:D017695), neuronal apoptosis (MESH:D065703), cognitive impairment (MESH:D003072), necrotic (MESH:D009336), spinal cord injury (MESH:D013119), corneal carcinoma (MESH:D065306), osteoarthritis (MESH:D010003), adipose tissue (MESH:D018205), obese (MESH:D009765), sciatic nerve defects (MESH:D020426), BD (MESH:D001528), liver fibrosis (MESH:D008103), bone defect (MESH:D001847), cerebral infarction (MESH:D002544), tumour (MESH:D009369), cerebral ischemia (MESH:D002545), diabetic wounds (MESH:D003920), gastrointestinal mucosal injury (MESH:D005767), allergic symptoms (MESH:D063926), skin injury (MESH:D000069836), reperfusion injury (MESH:D015427), fibrosis (MESH:D005355), inflammation (MESH:D007249), diabetic periodontitis (MESH:D010518), degenerative diseases (MESH:D019636), trauma (MESH:D014947)
- **Chemicals:** calcium (MESH:D002118), nitric oxide (MESH:D009569), glucose (MESH:D005947), 5-ethynyl-2'-deoxyuridine (MESH:C031086), agarose (MESH:D012685), PGE2 (MESH:D015232), Sucrose (MESH:D013395), Lipids (MESH:D008055), glutamine (MESH:D005973), citrate (MESH:D019343), water (MESH:D014867), malondialdehyde (MESH:D008315), phosphatidylcholine (MESH:D010713), polyacrylamide (MESH:C016679), phosphatidylserine (MESH:D010718), hydroxyapatite (MESH:D017886), triglycerides (MESH:D014280), poly (I: C) (MESH:D011070), EDTA (MESH:D004492), lactate (MESH:D019344), sphingomyelin (MESH:D013109), dextran (MESH:D003911), EVsABPC (-)
- **Species:** Cervidae (deer, family) [taxon 9850], Oryctolagus cuniculus (domestic rabbit, species) [taxon 9986], Cervus elaphus (red deer, species) [taxon 9860], Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090], Rattus norvegicus (brown rat, species) [taxon 10116], Macaca mulatta (rhesus macaque, species) [taxon 9544]
- **Cell lines:** HACAT — Homo sapiens (Human), Spontaneously immortalized cell line (CVCL_0038)

## Full text

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## Figures

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## References

155 references — full list in the complete paper: https://tomesphere.com/paper/PMC12960187/full.md

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Source: https://tomesphere.com/paper/PMC12960187